Over the past seven years, scientists at the University of Pittsburgh and Carnegie Mellon University have work together investigating the pathophysiology of schizophrenia. We have acquired substantial experience in the organization and operation of a translational center focused at the interface of basic and clinical neuroscience, and we have established a milieu in which basic and clinical neuroscientists collaborative productively on multidisciplinary issues. Our plans for this renewal application represent not only the logical extension of the ongoing research activities of individual projects in our Center, but also include the synergistic research programs that have resulted from interactions among Center investigators. Consequently, this application contains descriptions of eight integrated research projects, supported by four cores. Through this program of research, we are attempting to test complementary aspects of the following central hypothesis: Certain cognitive abnormalities characteristic of schizophrenia are due to an impairment of functions dependent on the dorsolateral prefrontal cortex (DLPFC). These dysfunctions arise during development as a consequence of interrelated abnormalities in specific subsets of the glutamate, GABA and dopamine components of the DLPFC circuitry. This abnormalities lead to altered glutamateric output from the DLPFC to cortical association regions, mediodorsal thalamic nucleus and nucleus accumbens. This hypothesis guides the work conducted within each project, and is subject to modification by the results obtained from each project. As a result of our extensive interactions, all Center investigators are made are of the data that suggest modifications to the hypothesis, and they are then able to make appropriate adjustments in their study designs or experimental models. Thus,our objective is to operate in a truly bidirectional fashion such that individual projects both attend to and contribute to the central hypothesis. In addition, our plans reflect the continuing evolution of our Center as they incorporate novel research opportunities that have developed in association with the integration of new faculty into the Center, including senior scientists who recruitment to Pittsburgh was in part facilitated by our CNMD, as well as junior faculty whose research careers have developed within the context of our Center.